The non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used group of drugs in the history of medicine. Since the introduction of aspirin in 1899, about 20 of these drugs have become available for use in the United States and Europe. They are used for the relief of symptoms of arthritis, for acute musculoskeletal conditions, miscellaneous injuries, and post-operative pain management.
NSAIDs are effective for the management of acute postoperative pain relief. These agents can be used in combination with opioid analgesics and local anesthetics for the relief of severe postoperative pain, where the combination results in reduced narcotic requirements and improved analgesia compared with opioids and/or local anesthetics alone. NSAIDs have been shown to be effective in a wide variety of post-operative pain states, including those following thoracotomy, major orthopedic surgery such as hip arthroplasty, upper and lower abdominal surgery, and minor outpatient surgery. The benefits of combining NSAIDs with opioid analgesics in the immediate post-operative period include not only improved analgesia, but also compounds benefits associated with narcotic sparing (improved respiratory function, reduction in nausea and vomiting, and reduced sedation). It has been suggested that NSAIDs may improve not only the quality but also the speed of recovery. By adding the NSAIDs to a routine analgesic armamentarium, the goal of preventing or eliminating post-operative pain, rather than only reducing post-operative pain, can be achieved.
However, the overall utility of NSAIDs is limited by the need to avoid dose-related side effects and by their mechanism of action. NSAIDs are extensively protein bound (>90%) and their effectiveness varies according to serum albumin and total protein. Some of the potential complications of NSAIDs are untoward effects due to a decrease in synthesis of various beneficial prostaglandins. This may cause a reduction of renal blood flow, especially in patients with heart failure and/or renal insufficiency, lead to gastric mucosal irritation, liver toxicity, and the inhibition of platelet aggregation. These potential complications of NSAIDs have caused clinicians to restrict the dosage of NSAIDs.
While NSAIDs are effective in reducing inflammation and inducing analgesia, the conventional oral dosage forms of these drugs characteristically have short half-lives and irritate the gastric mucosa. A major limitation with the use of NSAIDs is the high prevalence of gastrointestinal irritation. This problem ranges in severity from minor irritation to gastritis, duodenitis, and frank ulcerations with bleeding. The symptoms usually manifest themselves as “pain” or “distress.” These symptoms are often so severe and frequent, especially in the elderly, that they result in discontinuing NSAID therapy.
Site-specific (but not sustained release) delivery of NSAIDs has been tested by infiltration of various types of surgical wounds by many groups (Ben-David et al., 1995, Br. J. Anaesth. 75:409-412; Bosek et al., 1996, Ann. Surg. Oncol. 3:62-66; Knudsen et al., 1995, Br. J. Anaesth. 75:286-8; Lin et al., 1998, Acta Anaesth. Sin. 36:23-9; Mikkelsen et al., 1996, Anesth. Analg. 83:1239-43). No prospective randomized trials have been performed to demonstrate that such an approach is effective and limits complications; however, the bulk of evidence supports this site-specific approach. In 2001, a comprehensive review of the literature on the local infiltration of NSAIDs was written by Romsing (Romsing et al., 2001, Acta Anaesthesiol. Scand. 44:672-83), and in 2007, De Kock et. al. published a clinical trial comparing continuous wound infiltration with diclofenac after cesarean delivery and showed that it was more effective than ropivacaine continuous wound infiltration with intravenous (iv) diclofenac.
Romsing reviewed 16 randomized, controlled, double blind trials of site-specific NSAIDs (for a total of 884 patients). The treatments were by intra-articular injection, in intravenous regional anesthesia and wound infiltration (5 studies). The results showed that local delivery of NSAIDs was better than placebo in 4 studies and equal in 1, that local delivery of NSAIDs was better than systemic delivery of NSAIDs in 2 studies and equal in 3, and that, overall, the 24-hour consumption of supplemental analgesics was reduced by 60% by patients receiving local NSAIDs.
The above considerations demonstrate that there is a pressing need for improved products to relieve pain after surgery. There is ample evidence that NSAIDs have a peripheral mode of action. NSAID efficacy may be improved through sustained release and higher local concentration. NSAID safety may be improved through site-specific delivery that minimizes systemic effects and could provide the following advantages constant local analgesia without debilitating breakthrough pain, predictable analgesia since local binding of drug to protein will reduce individual variability in dose-response, avoidance/minimization of the complications of opiates and systemic NSAIDs, and allow patients to be discharged earlier from same-day surgery and return to work more quickly.
There are very few biopolymers in widespread use for the development of sustained release, injectable or implantable formulations of drugs. The most commonly employed resorbable biopolymers are poly(lactic) acid (PLA), poly(glycolic) acid (PGA), copolymers of the two (PLGA), and collagen. Two others are in limited use: polycaprolactone (a component of certain products with regulatory approval only in Europe) and one polyanhydride compound that comprises the Gliadel Wafer® marketed by Guilford Pharmaceuticals.
Lactic and glycolic acid-based polymers are some of the most commonly employed synthetic polymers in the development of drug delivery vehicles for use in humans despite their limitations. The most pressing problem is the drug “burst” that occurs soon after implantation. Most of the drug leaches out of the polymer vehicle within the first 24-48 hours of implantation as a result of incompatibility between drug and polymer. Other significant problems include: drug instability due to the acidic nature of the polymer, formulation techniques that use organic solvents and thus denature proteins and peptides, and site injection irritation of the initial biomaterial. The acidity of the lactic and glycolic acid breakdown products may also be deleterious to cartilage.
The physicochemical properties of the polymer in a sustained release formulation controls the fundamental behavior of the system. Since the number of biodegradable polymers available for drug delivery is very small, and the existing development methods for controlled delivery systems rely heavily on the currently used polymers, most new development work focuses on novel processes or excipients to control drug release profiles from those existing materials. For example, polylactic acid (PLA) (D&L forms), polyglycolic acid (PGA) (D&L forms) are currently the most widely used materials in the development of degradable drug delivery systems. Interestingly, these materials were not developed originally for this application, but rather for manufacturing biodegradable sutures. Since this class of materials has little structural diversity, there is limited room to manipulate drug-polymer interactions and thus to alter release profiles.
Brocchini et al., 1997, J. Amer. Chem. Soc. 119:4553-4554 described a class of polymers known as polyarylates that were formed by the combinatorial synthesis of 14 different tyrosine-derived diphenols with 8 different dicarboxylic acids to give a 112 member library of strictly alternating A-B type copolymers. These polyarylates are biocompatible and biodegradable. The dicarboxylic acids are naturally occurring metabolites like adipic acid and succinic acid. Since the polymers contain an ester linkage in the backbone, they are biodegradable and their degradation products, tyrosine, desaminotyrosine, and the dicarboxylic acids, all have known toxicity profiles. The polymers produce significantly less acid during their degradation process than the PLA and PGA families. Systematic variations in polymer properties can be obtained by varying the nature of the pendant group attached to the C-terminus of the tyrosine diphenol and the methylene groups in the dicarboxylic acid.